This invention relates to an implantable biomedical sensor device for measuring in vivo the presence and/or concentration of physiological substances, in particular the concentration of glucose, in a human or animal body.
The traditional glucose sensors are based on the oxidation of glucose by oxygen in the presence of the redox enzyme glucose oxidase (GOd). The flavin adenine dinucleotide (FAD) center of glucose oxidase is reduced to FADH by glucose (reaction 1). The regeneration of the enzyme occurs through reduction of oxygen to hydrogen peroxide (reaction 2). EQU GOd-FAD+glucose.fwdarw.GOd-FADH2+gluconate (1) EQU GOd-FADH2+O2.fwdarw.GOd-FAD+H2O2 (2)
The enzyme glucose oxidase is immobilized in gels or membranes which cover an electrode. The glucose content is determined indirectly in one of the following ways:
1. Detection of the decrease in oxygen with a Clark oxygen electrode. PA0 2. Detection of the hydrogen peroxide production with a hydrogen peroxide electrode.
A great disadvantage of this method is the sensitivity to the oxygen pressure of the environment.
A drawback of this technique is that hydrogen peroxide degrades the redox enzyme. Another drawback is the high voltage that must be applied, rendering the sensor sensitive to other electroactive components (for instance ascorbic acid) present in biological fluids. Often, biological fluids also contain the enzyme catalase, which breaks down hydrogen peroxide.
In a second generation of glucose sensors, mediators (ferrocene and derivatives) are utilized, which provide for the electron transfer between the redox enzyme and the electrode. The advantage of the use of mediators is that the measurement can be performed at a relatively low voltage, e.g. 350 mV, instead of 800 mV. As a result, by-reactions contribute to a lesser extent to the total current measured. The regeneration of the reduced flavin in glucose oxidase occurs through reduction of the mediator (reaction 3). The reduced mediator is subsequently oxidized electrochemically (reaction 4). EQU GOd-FADH2+2 MedOx.fwdarw.GOd-FAD+2 MedRed+2 H+ (3) EQU 2 MedRed.fwdarw.2 MedOx+2 electrons (at the anode) (4)
Sensors which are based on this principle have the disadvantage that the mediator disappears from the system. Moreover, usable mediators are often toxic, rendering in vivo measurement impossible. Recently, TNO (Dutch Organization for Applied Scientific Research) and the Catholic University of Nijmegen have developed a third generation of glucose sensors, involving direct electron transfer between the redox enzyme and an electrode via a conductive polymer. The basis of the sensor is a filtration membrane having cylindrical pores (Cyclopore, pore diameter 600 nm). By a specially developed polymerization process, tile pores of the membrane are coated with polypyrrole, so that hollow fibers of conductive polymer extend perpendicularly through the membrane and are in contact with the measuring fluid. The glucose oxidase is immobilized in the fibers, permitting direct electron transfer between the redox enzyme and the polymer. The location of the enzyme in the pores further provides protection of the enzyme against any influences of the environment, so that it can retain its active structure. After the enzyme has oxidized a glucose molecule (reaction 1), the reduced enzyme can be re-oxidized by transferring electrons to the conductive polymer.
It is noted that implantable electronic responders per se are already known. Dutch patent application 8701541, for instance, discloses the use of an implantable responder for the identification of livestock. Also, implantable responders are already utilized in practice for the identification of cattle and pigs. The known implantable responders are arranged in a glass tube melted up at its ends and comprise a resonant circuit whose coil at least partly constitutes the antenna for receiving an electromagnetic interrogation field generated by a transmitter or a transmitter/receiver. The interrogation field can bring the resonant circuit into resonance and the alternating voltage generated across the resonant circuit is used, after being rectified, as supply voltage for the digital circuits of the responder. The digital circuits comprise a code signal generator and can further comprise a clock pulse shaper. However, the clock pulses can also be derived directly from the tops of the alternating voltage across the resonant circuit. After receiving supply voltage and clock pulses, the code signal generator generates a binary code signal, which is used to control a switching means, for instance a transistor. The switching means is connected to the resonant circuit and can modulate the resonant frequency and/or the damping of the resonant circuit in the rhythm of the binary code signal. This modulation can be detected by a transmitter/receiver or by a separate receiver. These techniques are known per se. One example of a suitable responder is disclosed in U.S. Pat. No. 4,196,418, which is considered to be incorporated herein as a reference.